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Blood, 15 July 2001, Vol. 98, No. 2, pp. 467-474
TRANSPLANTATION
Requirements for the promotion of allogeneic engraftment by
anti-CD154 (anti-CD40L) monoclonal antibody under
nonmyeloablative conditions
Patricia A. Taylor,
Christopher J. Lees,
Herman Waldmann,
Randolph J. Noelle, and
Bruce R. Blazar
From the Department of Pediatrics, Division of Bone
Marrow Transplantation, University of Minnesota Cancer Center,
Minneapolis; the Department of Pathology, University of Cambridge,
United Kingdom; and the Department of Microbiology, Dartmouth Medical
College, Hanover, NH.
The promotion of alloengraftment in the absence of global immune
suppression and multiorgan toxicity is a major goal of transplantation. It is demonstrated that the infusion of a single modest bone marrow dosage in 200 cGy-irradiated recipients treated with anti-CD154 (anti-CD40L) monoclonal antibody (mAb) resulted in chimerism levels of
48%. Reducing irradiation to 100 or 50 cGy permitted 24% and 10%
chimerism, respectively. In contrast, pan-T-cell depletion resulted in
only transient engraftment in 200 cGy-irradiated recipients. Host
CD4+ cells were essential for alloengraftment as depletion
of CD4+ cells abrogated engraftment in anti-CD154-treated
recipients. Strikingly, the depletion of CD8+ cells did not
further enhance engraftment in anti-CD154 mAb-treated recipients in a
model in which rejection is mediated by both CD4+ and
CD8+ T cells. However, anti-CD154 mAb did facilitate
engraftment in a model in which only CD8+ T cells mediate
rejection. Furthermore, CD154 deletional mice irradiated with 200 cGy
irradiation were not tolerant of grafts, suggesting that engraftment
promotion by anti-CD154 mAb may not simply be the result of CD154:CD40
blockade. Together, these data suggest that a CD4+
regulatory T cell may be induced by anti-CD154 mAb. In contrast to
anti-CD154 mAb, anti-B7 mAb did not promote donor engraftment. Additionally, the administration of either anti-CD28 mAb or anti-CD152 (anti-CTLA-4) mAb or the use of CD28 deletional recipients abrogated engraftment in anti-CD154 mAb-treated mice, suggesting that balanced CD28/CD152:B7 interactions are required for the engraftment-promoting capacity of anti-CD154 mAb. These data have important ramifications for
the design of clinical nonmyeloablative regimens based on anti-CD154
mAb administration.
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